CMA: Network plasticity in acquired epileptogenesis

CMA：获得性癫痫发生中的网络可塑性

• 批准号: 10013745
• 负责人: Peyman Golshani
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013745
• 关键词: Adult; Affect; Animals; Anticonvulsants; Biological Markers; Brain; Calcium; Cell Death; Cells; Chronic; Code; Cognitive; Cognitive deficits; Communication; Complex; Computer Models; Craniocerebral Trauma; D Cells; Development; Devices; Disease; Electrophysiology (science); Epilepsy; Epileptogenesis; Excision; Fire - disasters; GABA Receptor; Goals; High Frequency Oscillation; Hippocampus (Brain); Image; Imaging Device; Impaired cognition; In Vitro; Injury; Interneurons; Intervention; Laboratories; Lead; Learning; Measures; Memory; Mental Depression; Microscope; Moods; Neurons; Operative Surgical Procedures; Parvalbumins; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Physiological; Pilocarpine; Population; Recurrence; Seizures; Slice; Somatostatin; Source; Status Epilepticus; Synapses; Techniques; Temporal Lobe Epilepsy; Time; Veterans; War; axonal sprouting; cell type; comorbidity; disability; excitatory neuron; extracellular; hippocampal pyramidal neuron; immunocytochemistry; in vivo; inhibitory neuron; military veteran; miniaturize; neocortical; neural circuit; open source tool; optogenetics; patch clamp; place fields; prevent; receptor expression; recruit; side effect; therapy development; tool; two-photon

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and a major source of disability in the veteran population as it is frequently caused by war-time head injuries. More than 1/3 of TLE patients do not respond to anticonvulsant medications and many are not candidates for epilepsy surgery. Therefore, new treatments are needed to prevent the development of epilepsy after the initial insult. Yet, the mechanisms that lead to the development of epilepsy during the period directly after status epilepticus (SE) are still poorly understood. A deep and precise understanding of these mechanisms is critical for development of interventions that can treat temporal epilepsy without the side-effects of medications and potential disability from large surgical resections. To determine the network dynamic changes in specific cell types during the earliest period after SE, we have developed a miniaturized microscope that is completely integrated with a high channel extracellular electrophysiology recording device (E-Scope). We hypothesize that hypersynchronous firing of parvalbumin positive (PV+) and progressive decreased engagement of somatostatin+ (SOM+) interneurons emerge during the epileptogenic period after the insult. We also hypothesize that these pathological circuit dynamics in both excitatory and inhibitory neurons will be readily observed during 200-400 Hz high frequency oscillations (HFOs) have been shown to be a biomarker for hyper-excitable epileptic circuit. In Aim 1 we will measure how PV+ and SOM+ neurons become activated during pathological fast ripples and physiological sharp-wave ripples through the epileptogenic period. In Aim 2, we will measure the precision of spatial coding by excitatory neurons and the reactivation of ensembles during physiological sharp-wave ripples and pathological fast ripples through the epileptogenic period. This information will be critical for identifying the cell specific targets for interventions to prevent epileptogenesis. Overall Strategy: The overall goal of our collaborative merit proposal is to determine the key changes in hippocampal and neocortical circuitry that promotes the development of epilepsy and cognitive dysfunction after the initial insult. Aims of Other Proposals: 1. Wasterlain will use immunocytochemical techniques, including EM immunocytochemistry, to quantify changes in the GABA receptor expression at the synapse and in the peri-synaptic space. 2. Naylor will use in-vitro slice patch clamp recordings, optogenetics, and computational modeling to understand how the functional connectivity of different interneuron types changes during this key period. 3. Smirnakis will use a combination of electrophysiological techniques and in-vivo mesoscopic two-photon calcium imaging to track the activity patterns of neocortical neurons during this period, to understand how hippocampal-cortical communication changes and drives the development of epilepsy. All studies are independent, yet deeply inform each other, as a multi- dimensional understanding will be key for making progress in this highly complex and disabling disorder.

颞叶癫痫（TLE）是成人最常见的癫痫形式，也是导致残疾的主要原因。 退伍军人群体，因为它是经常造成的战争时期头部受伤。超过1/3的TLE患者没有 对抗惊厥药物有反应，许多人不适合癫痫手术。因此，新 需要治疗以防止在初始损伤后癫痫的发展。然而， 导致癫痫发展期间直接发生癫痫持续状态（SE）的情况仍然不佳 明白深入而准确地了解这些机制对于制定干预措施至关重要 可以治疗颞叶癫痫，而没有药物的副作用和大型手术的潜在残疾， 切除术为了确定在SE之后的最早时段期间特定小区类型中的网络动态变化， 我们开发了一种小型化的显微镜， 细胞外电生理记录装置（E-Scope）。我们假设超同步放电 小白蛋白阳性（PV+）和生长抑素+（SOM+）中间神经元的参与进行性减少 在损伤后的癫痫发作期出现。我们还假设这些病理回路 在200-400 Hz的高频下，将容易观察到兴奋性和抑制性神经元的动力学 振荡（HFO）已被证明是超兴奋性癫痫回路的生物标志物。在目标1中， 测量PV+和SOM+神经元如何在病理性快速波动和生理性快速波动期间被激活。 在癫痫发作期产生尖锐的波动在目标2中，我们将测量空间编码的精度 通过兴奋性神经元和重新激活的合奏在生理尖锐波波纹， 癫痫发作期的病理性快速波动这些信息对于识别细胞至关重要 预防癫痫发生的干预措施的具体目标。总体战略：我们的总体目标 合作的价值建议是确定海马和新皮层电路的关键变化， 在最初的损伤后促进癫痫和认知功能障碍的发展。其他提案的目的： 1. Wasterlain将使用免疫细胞化学技术，包括EM免疫细胞化学，以量化变化 GABA受体在突触和突触周围空间的表达。2. Naylor将使用体外切片 膜片钳记录，光遗传学和计算建模，以了解功能连接如何 不同类型的中间神经元在这个关键时期发生了变化。3. Smirnakis将使用一种组合， 电生理技术和体内介观双光子钙成像来跟踪活动模式 在这一时期的新皮层神经元，以了解大脑皮层的沟通如何变化， 导致癫痫的发展所有的研究都是独立的，但彼此深入了解，作为一个多- 三维理解将是在这种高度复杂和致残性疾病中取得进展的关键。